Type 1 Diabetes (“T1D”) is an autoimmune disease in which the body's own immune system attacks and destroys the insulin-producing beta cells in the pancreas. It is estimated that T1D affects as many as 3 million people in the U.S. alone, with 80 new patients diagnosed every day. The rate of T1D incidence among children under the age of 14 is estimated to increase by 3% annually worldwide. Although careful and tight control of blood glucose level by injections or infusion of exogenous insulin allows a T1D patient to stay alive, the approach requires constant attention and strict compliance. It does not cure the disease or prevent its many devastating effects such as blindness, hypertension, kidney disease, neuropathy, vascular disease, heart disease, and stroke (The Diabetes Control and Complications Trial Research Group, “The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus,” N. Engl. J. Med. 329:977-986 (1993) and Writing Team for the Diabetes Complications Trial/Epidemiology of Diabetes & Complications Research, “Sustained Effect of Intensive Treatment of Type 1 Diabetes Mellitus on Development and Progression of Diabetic Nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study,” JAMA 290:2159-2167 (2003)).
Transplantation of islet cells provides a potential alternative treat treatment for T1D and has been shown to restore normoglycemia (Shapiro et al., “Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen,” N. Engl. J. Med. 343:230-238 (2000) and Shapiro et al., “International Trial of the Edmonton Protocol for Islet Transplantation,” N. Engl. J. Med. 355:1318-1330 (2006)). However, to avoid immune rejections, the patients need to take long-term immunosuppressive drugs that are known to cause deleterious side effects (Weir et al., “Scientific and Political Impediments to Successful Islet Transplantation,” Diabetes 46:1247-1256 (1997) and Naftanel et al., “Pancreatic Islet Transplantation,” PLoS Med. 1:e58 (2004)). The wide application of islet cell transplantation is also limited by a great shortage of appropriate donors (Weir et al., “Scientific and Political Impediments to Successful Islet Transplantation,” Diabetes 46:1247-1256 (1997) and Naftanel et al., “Pancreatic Islet Transplantation,” PLoS Med. 1:e58 (2004)).
Transplantation of encapsulated, immuno-protected islet cells is a much more attractive and extremely promising way to reverse T1D (Chang, “Therapeutic Applications of Polymeric Artificial Cells,” Nat. Rev. Drug Discov. 4:21-235 (2005); Orive et al., “Cell Encapsulation: Promise and Progress,” Nat. Med. 9:104-107 (2003); and Calafiore, “Alginate Microcapsules for Pancreatic Islet Cell Graft Immunoprotection: Struggle and Progress Towards the Final Cure for Type 1 Diabetes Mellitus,” Expert Opin. Biol. Ther. 3:201-205 (2003)). Islet cell transplantation avoids life-long immunosuppression, and also allows the use of other types of cells such as xenogeneic islets from pigs (Brandhorst et al., “Isolation of Islands of Langerhans from Human and Porcine Pancreas for Transplantation to Humans,” Zentralbl. Chir. 123:814-822 (1998); O'Sullivan et al., “Islets Transplanted in Immunoisolation Devices: A Review of the Progress and the Challenges that Remain,” Endocr. Rev. 32:827-844 (2011); and Dufrane et al., “Macro- or Microencapsulation of Pig Islets to Cure Type 1 Diabetes,” World J. Gastroenterol. 18:6885-6893 (2012)) or stem cell-derived ones (Kroon et al., “Pancreatic Endoderm Derived from Human Embryonic Stem Cells Generates Glucose-Responsive Insulin-Secreting Cells In vivo,” Nat. Biotechnol. 26:443-452 (2008) and Rezania et al., “Maturation of Human Embryonic Stem Cell-Derived Pancreatic Progenitors Into Functional Islets Capable of Treating Pre-Existing Diabetes in Mice,” Diabetes 61:2016-2029 (2012)). The encapsulating material or device protects the islets from the host immune rejection while simultaneously allowing facile mass transfer to maintain their survival and function.
Despite the huge research efforts worldwide and the significant progress that has been made in the last three decades, clinical application of encapsulation of islets cells has remained elusive due to a lack of translatable encapsulation systems (Scharp et al., “Encapsulated Islets for Diabetes Therapy: History, Current Progress, and Critical Issues Requiring Solution,” Adv. Drug Deliv. Rev. 67-68:35-73 (2013)). Currently, there are two major types of islet cell encapsulation systems: macroscopic devices and hydrogel microcapsules, both of which unfortunately have serious limitations. The macroscopic encapsulation devices, such as diffusion chambers (Geller et al., “Use of an Immunoisolation Device for Cell Transplantation and Tumor Immunotherapy,” Ann. N.Y. Acad. Sci. 831:438-451 (1997)), hydrogel sheet (Dufrane et al., “Alginate Macroencapsulation of Pig Islets Allows Correction of Streptozotocin-Induced Diabetes in Primates Up to 6 Months Without Immunosuppression,” Transplantation 90:1054-1062 (2010)) or porous polymer hollow tubes (Lacy et al., “Maintenance of Normoglycemia in Diabetic Mice by Subcutaneous Xenografts of Encapsulated Islets,” Science 254:1782-1784 (1991)) are often bulky or fragile, and suffer from insufficient biocompatibility and inadequate mass transfer (Colton, “Implantable Biohybrid Artificial Organs,” Cell Transplant. 4:415-436 (1995); Kiihtreiber et al., Cell Encapsulation Technology and Therapeutics, Birkhauser, Boston, 1999; Vaithilingam et al., “Islet Transplantation and Encapsulation: An Update on Recent Developments,” Rev. Diabet. Stud. 8:51-67 (2011); and Soon-Shiong, “Treatment of Type I Diabetes Using Encapsulated Islets,” Adv. Drug Deliv. Rev. 35:259-270 (1999)).
Alginate hydrogel microcapsules, on the other hand, are easy to transplant, have larger surface area for mass transfer, and significant progress has been made recently on their biocompatibility and long term function (Calafiore, “Alginate Microcapsules for Pancreatic Islet Cell Graft Immunoprotection: Struggle and Progress Towards the Final Cure for Type 1 Diabetes Mellitus,” Expert Opin. Biol. Ther. 3:201-205 (2003); Vaithilingam et al., “Islet Transplantation and Encapsulation: An Update on Recent Developments,” Rev. Diabet. Stud. 8:51-67 (2011); Smink et al., “Toward Engineering a Novel Transplantation Site for Human Pancreatic Islets,” Diabetes 62:1357-1364 (2013); Jacobs-Tulleneers-Thevissen et al., “Sustained Function of Alginate-Encapsulated Human Islet Cell Implants in the Peritoneal Cavity of Mice Leading to a Pilot Study in a Type 1 Diabetic Patient,” Diabetologia 56:1605-1614 (2013); and Dolgin, “Encapsulate This,” Nat. Med. 20:9-11 (2014)). However, a major challenge is that after the capsules are transplanted, often in high number (˜100,000) within the peritoneal cavity, it is almost impossible to reliably and completely retrieve or replace them in the event of medical complications or transplant failure (Calafiore, “Alginate Microcapsules for Pancreatic Islet Cell Graft Immunoprotection: Struggle and Progress Towards the Final Cure for Type 1 Diabetes Mellitus,” Expert Opin. Biol. Ther. 3:201-205 (2003); Vaithilingam et al., “Islet Transplantation and Encapsulation: An Update on Recent Developments,” Rev. Diabet. Stud. 8:51-67 (2011); Smink et al., “Toward Engineering a Novel Transplantation Site for Human Pancreatic Islets,” Diabetes 62:1357-1364 (2013); and Jacobs-Tulleneers-Thevissen et al., “Sustained Function of Alginate-Encapsulated Human Islet Cell Implants in the Peritoneal Cavity of Mice Leading to a Pilot Study in a Type 1 Diabetic Patient,” Diabetologia 56:1605-1614 (2013)). This raises patients' concerns over the permanent implantation of biomaterials and foreign cells within their body. There is also a risk of potential teratoma formation when stem cells are used. Additionally, the inability to retrieve the entire implant makes it impossible for physicians and researchers to examine the transplant in its entirety after failure.
Hydrogel microfibers, such as those made from alginate, have received much attention recently as a potentially biocompatible, high surface area platform to encapsulate cells for various applications (Onoe et al., “Meter-Long Cell-Laden Microfibres Exhibit Tissue Morphologies and Functions,” Nat. Mater. 12:584-590 (2013); Raof et al., “One-Dimensional Self-Assembly of Mouse Embryonic Stem Cells Using an Array of Hydrogel Microstrands,” Biomaterials 32:4498-4505 (2011); Lee et al., “Synthesis of Cell-Laden Alginate Hollow Fibers Using Microfluidic Chips and Microvascularized Tissue-Engineering Applications,” Small 5:1264-1268 (2009); Zhang et al., “Creating Polymer Hydrogel Microfibres with Internal Alignment Via Electrical and Mechanical Stretching,” Biomaterials 35(10):3243-3251 (2014); Yu et al., “Flexible Fabrication of Biomimetic Bamboo-Like Hybrid Microfibers,” Adv. Mater. 26(16):2494-2499 (2014)). These microfibers are generally produced by microfluidic approaches. They are scalable from millimeters to meters long and can be further woven using thin capillaries and fluidic flows (Onoe et al., “Meter-Long Cell-Laden Microfibres Exhibit Tissue Morphologies and Functions,” Nat. Mater. 12:584-590 (2013)). However, the intrinsic mechanical weakness of hydrogel materials, especially those suitable for cell encapsulation applications, and a high aspect ratio make hydrogel microfibers easy to break and difficult to handle. Both issues are significant concerns for eventual clinical applications.
Host recognition and subsequent foreign body responses can cause the failure of transplanted biomedical devices. Even though alginate hydrogel has been considered a relatively biocompatible material and has been used in many clinical trials, it still can cause foreign body reactions that lead to fibrotic cellular overgrowth and collagen deposition. It is known that the geometry of the transplanted materials can significantly influence fibrosis.
The present invention overcomes past deficiencies in the creation of hydrogel implants for treatment of diabetes, e.g., type 1 diabetes or type 2 diabetes.